Rumor Viruses author weighs in on XMRV debate

I'm sure you're not arguing that the last 30 years have been characterized by open-minded HEALTHY skepticism. I agree 100% with Kurt - the tough questions need to be made as tough as possible and answered as thoroughly as possible. This would make for a thorough investigation, not one driven by "true believers" of any variety.

What we HAVE had with CFS is a lot of "True Disbelievers" - those unwilling to vigorously investigate evidence of a biological cause because of an assumption that there really isn't one. That is not healthy skepticism - that is denialism that amounts to a superstition.

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I tend to agree with this, but I guess he is a UK guy, so many have their reservations, since things are very slow to change in that country and research is abysmal?!

I haven't read the article - somehow I missed it - but surely Alter/Lo attempted to address some of the concerns in it in their letter to PNAS. Does their response clarify things at all - anybody know? I thought they did a good job but I am only a laymen - could have missed something.

I agree with Kurt that too little has been made of confounding possibilities and looking back it's true that in general the WPI did present the virus in a very positive light. Most researchers fall over backwards in their attempts to not to be too positive. As I remember there are two types of general errors; overstating your findings and understating them. The first -overstating your findings - is by far considered the more serious boo-boo - which is why so many researchers are so painfully (to patients!) careful not to to be too positive about their study results.

With regards to this article while I found that it raised some good points I found it to be surprisingly lightweight. While it did point out some areas of concern it hardly present a rigorous examination of them. From the XMRV Buzz page

A Rumor of Viruses - Thirteen years ago John Weiss was burned by a viral discovery that, years later, turned out not to be one. The author of 'Rumor Viruses' he's made it his job to warn the research world of the perils of viral discovery. Now in this PubMedCentral article he's turned his attention to XMRV.

He makes the point that XMLV's (Xenotropic murine leukemia viruses)- which are distinct from, but closely related to XMRV's - are commonly found in labs that have done cancer research and may be widespread in laboratory reagents. He notes that the Hot Taq polymerase enzyme has mouse antibodies and can carry XMRV. (Check out the above article for Alter/Lo's response to the Taq question). Except for one other type of virus murine leukemia viruses are the most problematic because of their prevalence in the medical research worldp ie it's easy to contaminate a sample with them.

The most intriguing part of Weiss's essay concerns his own viral discovery that turned out not to be one. In that instance, as well, the putative virus was found in more sick patients than healthy controls - seemingly a clear sign that contamination had not occurred. As to how or why the contamination did occur, Weiss was never able to tell - the only idea he could come up with was that the ill patient samples had been handled more than the healthy control samples and that somehow allowed the contaminant entry. His story pointed out the cautionary tale that even labs that seem to do everything right can fail.

He notes that "If the healthy samples had come from strictly derived case-control collections in which the control vials were handled in exactly the same manner, for the same time and with the same frequency as the vials containing the clinical specimens (which has not been done for CFS), we might not have observed the bias towards detection in cases above controls." Reading Dr. Weisses recipe for success, however, does make one glad for the Singh study (and probably others) which are doing exactly as he recommends.

Another point he brings up is the apparent ease with which both the WPI group and Alter/Lo group found the viruses. Both were able to pick it up using a single round of PCR while other groups were unable to find any trace of it (or them) after two rounds of PCR - a good point that Alter/Lo responded to but which has yet to receive a definitive answer.

Dr. Weiss does bring up some good points but I found his paper to be surprisingly light; more an essay than a probing analysis of a problematic finding. There was no discussion of how effective the efforts of the WPI, NCI and now Alter/Lo labs to account for the presence of a possible contaminant were. There was no discussion about geographical differences in sequences or the possibilities of recombination or different primer sets. In the end Weiss took a rather anecdotal approach to warn the research world about this possibly spurious finding - not a convincing combination at all and one which I guess will do little to advance his cause. Certainly the 'opposition' can be more rigorous in their appraisal of XMRV.

I'm sure you're not arguing that the last 30 years have been characterized by open-minded HEALTHY skepticism. I agree 100% with Kurt - the tough questions need to be made as tough as possible and answered as thoroughly as possible. This would make for a thorough investigation, not one driven by "true believers" of any variety.

What we HAVE had with CFS is a lot of "True Disbelievers" - those unwilling to vigorously investigate evidence of a biological cause because of an assumption that there really isn't one. That is not healthy skepticism - that is denialism that amounts to a superstition.

I see no evidence of invisible elephants and think it's irresponsible to alarm the public by suggesting they may exist - regardless of the potential damage that could be caused if they did - any evidence you may have that suggests otherwise (inc footprints in butter, wrecked fridges, great steaming piles of elephant dung etc) was probably caused by contamination and as such would strongly suggest the non existence of your hypothesised invivble elphants - as an invisible animal specialist I would know if they existed and I dont - ergo they dont and cant exist

I agree with Kurt that too little has been made of confounding possibilities and looking back it's true that in general the WPI did present the virus in a very positive light.

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Not in their paper, which is what matters to other researchers. It did not "oversell" their positive findings, and the study was in fact designed to provide multiple corroborations of their PCR results and to reduce any potential contamination concerns.

I definitely agree with you about the Weiss article being lightweight. When a scientist raises concerns about flaws and potential artifact in another scientist's results, s/he is supposed to suggest an alternative experiment to rule out said artifact - which Weiss really does not, as even a multi-lab study wouldn't be immune to some of the vague concerns he raises - and to provide a critique of their own statement, e.g. point out the potential flaws in the contamination argument. No one who has raised contamination as an issue has done this so far.

Erlwein et al brought up the Taq polymerase issue already in their comment to PNAS, and as you mentioned Lo et al provided a very strong response.

Too worn out to critique Weiss's spiel thoroughly, but a few points on this paragraph of his:

"CSF [sic] patients would then be assured of having a recognized infection with the possibility of effective treatment - indeed, some of them are already so convinced they have started treatment with anti-retroviral drugs (first developed against HIV) in the hope of clearing infection and their symptoms. Blood banks would have to consider whether to screen donations for the implicated retroviruses. But before such steps could be justified, it will be essential to perform truly blinded tests on cases and proper controls in several laboratories. Profoundly disappointing as this would be for patients, without such additional studies, laboratory artifacts cannot be ruled out; also, with the signal exceptions of HIV and human T-lymphotrophic virus, the history of retroviral associations with human disease is not encouraging."

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(1) Blood bank donor screening does not have to wait on the results of his proposed studies; that is a public health precaution which needs to be instituted more swiftly than the slow wheels of science can turn (his own government's blood supply agency, by the way, will likely disagree with him on this matter).

(2) Carefully controlled antiretroviral trials technically do not have to wait until his proposed requirements are met, either.

(3) The Lombardi study was "truly blinded"; for him to to imply otherwise, as I believe he was (he clearly wasn't just referring to the Alter/Lo study) is deceptive.

(4) He does not mention the ongoing Blood Working Group on XMRV, which is a multi-laboratory coordinated study "with blinded tests on cases and proper controls". [By the way, what the heck is a "proper control"? Spiked water, like his colleague McClure used?]

(5) The fact that there is a history of false "retroviral associations with human disease" should have no bearing on a scientist's attitude towards current research in this area, unless specific mistakes from those failed efforts are being repeated. To say otherwise would be to bring unacceptable researcher bias into the equation (which, frankly, Weiss seems to be doing).

Weiss does NOT say that HotStart Taq Polymerase contains XMRV. He speculates that it might sometimes contain traces of X-MLVs, the mouse ERVs to which XMRV appears to be (in part) related.

I hope it's possible for you to edit that post on the XMRV Buzz page? :worried:

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Yes, technically you are correct and I will although since he was referring to XMRLV's which includes XMRV and since XMRV (and I grant MLV's) is the topic of note at this point - I imagine he brought the point up because he believes the Taq polymerase is contaminating the samples with XMRV - and it is why XMRV (and pMLV's) to show up in the WPI's and Alter/Lo findings. Ie - that's what he was saying without directly say so

Not in their paper, which is what matters to other researchers. It did not "oversell" their positive findings, and the study was in fact designed to provide multiple corroborations of their PCR results and to reduce any potential contamination concerns.

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No problems with the paper!

I definitely agree with you about the Weiss article being lightweight. When a scientist raises concerns about flaws and potential artifact in another scientist's results, s/he is supposed to suggest an alternative experiment to rule out said artifact - which Weiss really does not, as even a multi-lab study wouldn't be immune to some of the vague concerns he raises - and to provide a critique of their own statement, e.g. point out the potential flaws in the contamination argument. No one who has raised contamination as an issue has done this so far.

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I agree - not very rigorous! It's not like Mikovits and Ruscetti and Alter/Lo don't know all about the Taq problem etc. That should be easy to take care of because its so obvious. Nobody on that side has really done a point by point examination of the pro's and con's of the problem. Like I said when Coffin starts to turn - that's when I'll get worried.

Too worn out to critique Weiss's spiel thoroughly, but a few points on this paragraph of his:

(1) Blood bank donor screening does not have to wait on the results of his proposed studies; that is a public health precaution which needs to be instituted more swiftly than the slow wheels of science can turn (his own government's blood supply agency, by the way, will likely disagree with him on this matter).

(2) Carefully controlled antiretroviral trials technically do not have to wait until his proposed requirements are met, either.

(3) The Lombardi study was "truly blinded"; for him to to imply otherwise, as I believe he was (he clearly wasn't just referring to the Alter/Lo study) is deceptive.

(4) He does not mention the ongoing Blood Working Group on XMRV, which is a multi-laboratory coordinated study "with blinded tests on cases and proper controls". [By the way, what the heck is a "proper control"? Spiked water, like his colleague McClure used?]

(5) The fact that there is a history of false "retroviral associations with human disease" should have no bearing on a scientist's attitude towards current research in this area, unless specific mistakes from those failed efforts are being repeated. To say otherwise would be to bring unacceptable researcher bias into the equation (which, frankly, Weiss seems to be doing).

Yes, technically you are correct and I will although since he was referring to XMRLV's which includes XMRV and since XMRV (and I grant MLV's) is the topic of note at this point - I imagine he brought the point up because he believes the Taq polymerase is contaminating the samples with XMRV - and it is why XMRV (and pMLV's) to show up in the WPI's and Alter/Lo findings. Ie - that's what he was saying without directly say so

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The point is that no one has found XMRV in a mouse yet, or in any species other than humans. Same goes for the gag sequences found by Lo et al (whatever they belong to). Weiss merely speculates that mouse cell lines might be expressing as yet unidentifed murine ERVs that might include what we are currently calling XMRV or something with the Lo/Alter gag sequences, but it's conjecture on his part, based on the observation that his lab had found mouse tumor cells expressing certain X-MLVs (not XMRV, of course).

Like I said when Coffin starts to turn - that's when I'll get worried.

The point is that no one has found XMRV in a mouse yet, or in any species other than humans. Same goes for the gag sequences found by Lo et al (whatever they belong to). Weiss merely speculates that mouse cell lines might be expressing as yet unidentifed murine ERVs that might include what we are currently calling XMRV or something with the Lo/Alter gag sequences, but it's conjecture on his part, based on the observation that his lab had found mouse tumor cells expressing certain X-MLVs (not XMRV, of course).

Just when he thought he was out he was dragged back in - so much for retirement.

Right - good points - there's so much we don't know about what those sequences are referring to. Hopefully we'll get some interesting info from LO and Alter in the not too distant future. I'm sure they're really digging into those samples. Its a fascinating pest or pest group or swarm or whatever it is, that's for sure.

What a field day these people are having - denouncing seems their pleasure of any of the genuine researchers who seek only to understand and bring relief to millions. Recall visiting Darwins home in Kent and found the antagonisms to him in some circles much like that in ME. Despite all we are getting there.Thanks mostly to US researches we are well on the way.

Speaking of Darwin, did you know he was so sick he felt he was going to die, and was treated with water therapy and homeopathy and went on to write his great works?

"In early 1849, Charles Darwin was so ill that he was unable to work one of every three days, and after having various serious symptoms for two to twelve years, he wrote to a friend that he was dying."

Personally I liked the Rumor Viruses article a lot and thought it has merit, at least for considering. I don't think anybody's trying to shoot down good science. Good science proceeds through rigorous debate and weeding out incorrect hypotheses and eventually arriving at consensus. That's just how it works and it takes a bit of time.